Attention Deficit Hyperactivity Disorder (ADHD) is a genetically influenced brain disorder with a prevalence of 3-5% in school-age children. Affected sibling pairs and densely affected multi-generation families have been recruited from Colombia, South America, the US, and Germany. A genome-wide search for loci linked to ADHD has been completed and we have identified at least five regions in the human genome that contain genes to may contribute to ADHD (Arcos-Burgos et al. 2004). To date, we have complete clinical information on a total of over 600 small and large, multi-generation families, respectively (Palacio et al., 2004;Jain et al. 2006). We are now in the process to use the clinical and genome data to search for genes that contribute to ADHD. Recently, we have identified a gene that has the highest genetic contribution to ADHD to date. In the world-wide samples statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology and treatment of ADHD (Arcos-Burgos et al. 2010).